Characterization of the morphological and functional properties of human lymphocytes and monocyte-macrophages is essential for an understanding of their role in the normal immune response and in immunologic and neoplastic diseases. Cell subpopulations will be isolated and their electron microscopic, cytochemical and membrane receptor properties studied. Lymphocytes from normal individuals, patients with immunologic deficiency diseases and from their relatives will be incubated in vitro with phytomitogens and the mechanism of stimulation studied, with particular emphasis on defining cell subpopulations and the role of the plasma membrane in early events. The recognition of antigens and antibodies involving plasma-membrane receptors will be studied by the newly developed technique of freeze- etching which makes possible the study of cell membrane topography. This method is the only available means for the electron microscopic identification of membrane subunits. The characterization of cell membrane topography may be a means for identification of lymphoid cells in relation to their function, thymus and bone-marrow dependent. This method may also be a means for the classification of abnormal lymphoid cells. The erythrocyte plasma membrane and its antigenic components can be used as a model: our application of freeze-etch methodology in combination with ferritin-labelled antibody to erythrocyte antigenic sites (ABO blood groups) demonstrates the feasibility of this approach. These techniques will be applied to cells involved in the immune response (plasma membrane receptors for immunoglobulins, complement components and antigen). It may also be possible to further extend this methodology to the study of normal and abnormal cell-cell interaction in immunologic systems. This investigation has broad implications both for an understanding of the pathophysiology of immunologic diseases and for possible approaches to modification of the immune response in other clinical situations.